Key points

 

• In patients failing a TDF + FTC/3TC + EFV or NVP first-line regimen, the second-line should be TDF + 3TC/FTC + DTG (TLD).
• In patients with renal impairment or prior TDF nephrotoxicity failing an NNRTI regimen, options are TAF + FTC + DTG (if eGFR > 30 mL/min/1.73m²), ABC + 3TC + DTG, ABC + 3TC + DRV/r or ABC + 3TC + ATV/r.
• In patients failing TLD first-line with documented DTG resistance (rare) the second-line should be TDF + FTC/3TC + DRV/r
• We advise DRV/r 800 mg/100 mg once daily as the first choice PI if a PI is used in second-line therapy

Table 14 summarises the recommended second-line regimen to start in patients who have failed a first-line regimen consisting of two NRTIs + NNRTI.
 

Based on the results of the DAWNING trial, it is preferable to use a DTG-based regimen rather than a LPV/r regimen in second-line therapy. ²² In this trial, a second-line regimen of DTG + two NRTIs was superior in terms of virological suppression due to better tolerance than LPV/r + two NRTIs in patients who had failed a first-line regimen of NNRTI + two NRTIs. All patients enrolled in this trial had a resistance test performed at entry and had to have at least one fully active NRTI to be eligible.

Since the DAWNING trial, three trials have demonstrated the virological efficacy of maintaining the same NRTI backbone of TDF + 3TC from firstto second-line ART and only switching EFV to DTG. In the NADIA trial at 96 weeks, 92% of patients on second-line TLD has VL < 400 copies/mL, the same as patients on second-line TDF + 3TC + DRV/r. In this trial, maintaining TDF + 3TC from first- to secondline was superior in terms of VL suppression at 96 weeks, compared to switching the NRTI backbone to AZT + 3TC. Excellent virological outcomes were seen in patients with resistance to both TDF and 3TC on second-line TLD. ⁸³ In the VISEND trial, 83% of participants on second-line TLD had a VL < 1000 copies/mL at 48 weeks which was similar to patients on AZT + 3TC + ATV/r (82%) and higher than in patients on AZT + 3TC + LPV/r (69%). ⁹⁸ In stages 1 and 2 of the ARTIST trial conducted in South Africa, 82-86% of patients on second-line TLD had a VL < 50 copies/mL at 24 weeks. ^{100, 101}

If a boosted PI is used in second line (e.g. if DTG is not tolerated) we recommend DRV/r 800/100mg once daily as the PI of choice. It is associated with fewer gastro-intestinal side effects than LPV/r and is not associated with unconjugated hyperbilirubinaemia like ATV/r. It also has a higher genetic barrier to resistance than LPV/r or ATV/r. The second choice PI advised is ATV/r which has fewer gastro-intestinal side effects than LPV/r. LPV/r is only advised if a PI is required, and the patient is on RIF-based TB treatment – in this situation LPV/r should be double dosed at 800/200mg twice daily. ATV/r and DRV/r should not be co-administered with RIF.

The second-line regimen to commence in patients who have failed a first-line approach of two NRTIs + DTG is provided in Table 15.
 

If patients experience virological failure on a first-line DTG-based regimen, then we do not recommend switching to second-line therapy unless a resistance test is performed and demonstrates DTG resistance. This is because DTG is a very robust drug and resistance is very rare when used in triple-drug combination first-line therapy. Therefore, it is far more likely a VL > 50 copies/mL is due to adherence problems rather than resistance. If DTG resistance is demonstrated, then we then advise a regimen of two NRTIs + DRV/r. Usually this would be TDF + 3TC or FTC + DRV/r unless there is renal impairment or prior TDF nephrotoxicity. The NADIA trial reported high rates of virological success of this regimen and no development of PI resistance, even when there was resistance to both TDF and 3TC. ⁸³

Patients currently established on protease inhibitor-based second-line therapy

We recommend switching patients currently on a second-line LPV/r regimen, to a TLD regimen, particularly in patients experiencing gastrointestinal or other side-effects including dyslipidaemia. This switch will simplify the regimen and reduce pill burden. Clinical trials data ²² suggests better outcomes on a second-line DTG regimen compared with a secondline LPV/r regimen, driven by better tolerance. This recommendation is regardless of current VL, but see note of caution below.

There is direct evidence from the 2SD trial ¹⁰² that patients suppressed on a second-line PI regimen switched to a DTG second-line regimen maintained suppression equivalent to those randomised to continue the PI regimen (suppression remained >90% in both arms). In patients currently on a second-line ATV/r or DRV/r-based regimen, a switch to TLD could be considered, particularly in patients experiencing gastrointestinal or other side-effects. Trial findings suggest equivalent second-line outcomes with a TLD regimen and a DRV/r based-regimen ⁸³ and an ATV/rbased regimen. ⁹⁸ However, switching to TLD may reduce side effects and pill burden.

Patients who have renal impairment or prior tenofovir nephrotoxicity and who are on a LPV/r second-line regimen could be switched to TAF + FTC + DTG (if eGFR > 30 mL/min/1.73m²) or ABC + 3TC + DTG, to reduce side effects and provide a once daily regimen. It is important to note that the same direct evidence of virological efficacy for ABC + 3TC + DTG in second-line does not exist, as for TLD and, therefore, VL of patients should be monitored closely. In patients who have renal impairment or prior tenofovir nephrotoxicity, who are on DRV/r or ATV/r second line regimens we recommend maintaining their current regimen unless they are not tolerating the PI in which case one of the two regimens above could be considered.

Patients in whom caution should be applied before switching from a second-line PI regimen to a DTG regimen is those who have been on the PI regimen for more than 2 years and with 2 or more consecutive VL measurements above 1000 copies/mL. Such patients should have a resistance test done before switching as they may require a more robust regimen that includes DRV/r if they have acquired PI resistance mutations (see module 14).

Based on the findings of the NADIA trial, patients on AZT + 3TC + DTG second-line therapy should be switched to TLD. NADIA demonstrated that at 96 weeks TDF/3TC was superior to AZT/3TC as an NRTI backbone in second-line in terms of virological suppression. This appeared to be the case regardless of NRTI mutational profile present at first-line failure. ⁸³ If a patient has been on AZT + 3TC + DTG for over 2 years and has had 2 or 3 VL measurements > 1000 copies/mL then an integrase resistance test could be considered before switching to ensure there is still susceptibility to DTG.